Phytomedicine最新文献

{"title":"Inhibition of PKM2 by shikonin impedes TGF-β1 expression by repressing histone lactylation to alleviate renal fibrosis.","authors":"Tianya Xiang, Xijian Wang, Shujiao Huang, Kexin Zhou, Shengnan Fei, Bing Zhou, Kun Yue, Qingxin Li, Shengnan Xue, Yongyi Dai, Jing Zhang, Haoran Ni, Cheng Sun, Xinzhong Huang","doi":"10.1016/j.phymed.2024.156324","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156324","url":null,"abstract":"<p><strong>Background: </strong>Macrophage-myofibroblast transition (MMT) plays a significant role in the progression of renal fibrosis in chronic kidney disease (CKD), making inhibition of MMT a promising therapeutic strategy. Pyruvate kinase M2 (PKM2) and its metabolite lactate are implicated in the pathogenesis of renal fibrosis; however, the mechanisms through which they contribute to this process remain poorly understood.</p><p><strong>Purpose: </strong>To investigate the effects of PKM2 inhibition by shikonin on renal fibrosis and the underly mechanisms.</p><p><strong>Methods: </strong>Mice were subjected to unilateral ureteral obstruction (UUO) to establish a CKD model. Renal fibrosis was assessed using histochemistry and western blotting. The MMT and histone lactylation levels were evaluated by immunofluorescence and western blotting. The interaction between the Tgfb1 promoter and lactylated histone H3 (K18) was examined using chromatin Immunoprecipitation (ChIP).</p><p><strong>Results: </strong>PKM2 expression was significantly elevated in the renal tubular cells of UUO mouse kidneys, resulting in increased pyruvate and lactate production. Similarly, lactate levels were elevated in TGF-β1-treated TCMK-1 cells and in the serum of CKD patients. In UUO mice, treatment with shikonin, a potent PKM2 inhibitor, effectively reduced lactate production, alleviated renal fibrosis, decreased TGF-β1 expression, and suppressed the MMT process. Mechanistic studies revealed that lactate treatment stimulates Tgfb1 expression in TCMK-1 cells. Consequently, TGF-β1 in conditioned media from lactate-treated TCMK-1 cells promoted M2 macrophage polarization and upregulated fibrotic gene expression in RAW264.7 cells. Pharmacological intervention demonstrated that TGF-β1 activates the Smad3 pathway to drive the MMT process. In TCMK-1 cells, both lactate treatment and PKM2 overexpression induced Tgfb1 expression by promoting histone H3K18 lactylation.</p><p><strong>Conclusions: </strong>Our findings indicate that PKM2-induced excessive lactate production renal tubular cells contributes to renal fibrosis. Lactate promotes histone lactylation, leading to TGF-β1 expression in these cells, which subsequently activates the Smad3 pathway in macrophages, driving the MMT and fibrosis in the kidney. Therefore, targeting PKM2, as with shikonin treatment, may represent an effective therapeutic strategy for managing renal fibrosis in CKD.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156324"},"PeriodicalIF":6.7,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting the neuronal mechanisms of pinoresinol against methamphetamine addiction based on network and experimental pharmacology.","authors":"Shuyuan Fan, Yize Qi, Fukang Zhang, Yatong Shi, Kunfang Ma, Qihang Pan, Ai Jiang, Luanyue He, Junlong Zhang, Tengfei Ma, Li Zhou","doi":"10.1016/j.phymed.2024.156322","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156322","url":null,"abstract":"<p><strong>Background: </strong>Addiction is a chronic brain disease in which the underlying neuronal mechanism is characterized by drug-seeking and use. Flos Daturae (FD) and its components are used to treat addiction. However, the effective ingredients of FD that are linked to the neuronal mechanisms of seeking behavior remain unclear.</p><p><strong>Objective: </strong>We aimed to explore the effect and mechanism of the monomer ingredients of FD on methamphetamine (METH) addiction.</p><p><strong>Methods: </strong>The main chemical constituents and potential targets of FD were screened using LC-MS/MS and bioinformatics method. Molecular docking was used to screen the component of FD associated with the neuronal subtype mechanism. The effectiveness of the targets in related pathways was verified by behavioral experiment, immunofluorescence and Western blot. Electrophysiology was used to identify the functions of the ingredients of FD in D1-tdTomato and D2-eGFP transgenic mice.</p><p><strong>Results: </strong>There were 125 targets of 25 active components in FD, which included dopamine 1 receptor (D1R)/dopamine 2 receptor (D2R)/cAMP signaling pathway. Furthermore, we identified that pinoresinol (PINL) is a major component of FD targeting this signaling pathway. Moreover, PINL attenuated METH-induced seeking behavior and decreased expression of c-Fos in striatal D1R neurons, but not D2R neurons. Accordingly, PINL functionally reduced the over-excitation of D1R, but not D2R neurons. Finally, we clarified that D1R/PKA pathway is a critical factor mediating the effects of PINL on METH-induced seeking behavior.</p><p><strong>Conclusion: </strong>We revealed that PINL specifically targeted D1R/PKA signaling in D1R neurons and decreased METH-induced seeking behavior, providing a new strategy to treat addictive diseases.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156322"},"PeriodicalIF":6.7,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum \"Enhancement of gemcitabine efficacy by K73-03 via epigenetically regulation of miR-421/SPINK1 in gemcitabine resistant pancreatic cancer cells\" [Phytomedicine 2021:91:153711].","authors":"Abdullah Shopit, Xiaodong Li, Shisheng Wang, Mohammed Awsh, Mohammed Safi, Peng Chu, Jianlong Jia, Mohammed Al-Radhi, Salem Baldi, Fuhan Wang, Jiani Fang, Jinyong Peng, Xiaodong Ma, Zeyao Tang, Xiaohong Shu","doi":"10.1016/j.phymed.2024.156301","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156301","url":null,"abstract":"","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":" ","pages":"156301"},"PeriodicalIF":6.7,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Bushen Huoxue Yiqi formula alleviates cardiac fibrosis in ischemic heart failure through SIRT1/Notch1 pathway-mediated EndMT\" [Phytomedicine Journal 135 (2024) 156252].","authors":"Cong Chen, Jie Wang, Chengzhi Hou, Wenjing Lian, Xueying Zhu, Jun Hu, Chao Liu","doi":"10.1016/j.phymed.2024.156315","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156315","url":null,"abstract":"","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":" ","pages":"156315"},"PeriodicalIF":6.7,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Ilexchinene, a new seco-ursane triterpenoid from the leaves of Ilex chinensis with therapeutic effect on neuroinflammation by attenuating the MAPK/NF-κB signaling pathway\" [Phytomedicine 121 (2023) 155110].","authors":"Siyuan Shao, Ruofei Li, Kexin Wang, Wenqi Xia, Baosong Cui, Shuai Li","doi":"10.1016/j.phymed.2024.156320","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156320","url":null,"abstract":"","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":" ","pages":"156320"},"PeriodicalIF":6.7,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Xinkeshu formula restrains pathological cardiac hypertrophy through metabolic remodeling via AMPK/mTOR pathway.","authors":"Yi-Jing Zhao, Wen-Hui Wu, Kai-Ming Niu, Wen-Jiao Zhang, Shu-Rui Li, Rui-Long Bao, Kai-Ran Chen, Gaoxiang Ma, Baolin Liu, Lian-Wen Qi, Pingxi Xiao, An Pan","doi":"10.1016/j.phymed.2024.156309","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156309","url":null,"abstract":"<p><strong>Background: </strong>Xinkeshu (XKS) formula is a patented traditional Chinese medicine used to treat cardiovascular diseases for decades. However, little is known about its potential influence on heart metabolism under pathological conditions.</p><p><strong>Purpose: </strong>This study sought to explore the potential role of XKS in pathological cardiac hypertrophy, with a focus on metabolic remolding.</p><p><strong>Methods: </strong>We established pathological cardiac models in mice by transverse aortic constriction (TAC) and isoprenaline (ISO) challenge with continuous oral administration of XKS at specified doses for 4 weeks. In cultured cardiomyocytes, we observed the effects on metabolism and the mechanisms that underlie the process.</p><p><strong>Results: </strong>In the TAC model mice, oral administration of XKS restrained cardiac hypertrophy, indicated by decreases in heart mass and cardiomyocyte size. Meanwhile, XKS also suppressed fetal gene induction and cardiac fibrotic response. Echocardiography examination showed that XKS improved heart contractility and diastolic function. Similar results were observed in the hearts of mice subjected to isoprenaline challenge. In cultured cardiomyocytes, angiotensin II stimulation induced cardiomyocytes enlargement and fetal gene induction, which were normalized by XKS. XKS reduced cellular energy charge to induce AMPK activation, which inactivated mTOR by modification of phosphorylation, contributing to attenuating cardiac hypertrophy. Following cardiac hypertrophy, metabolism was reprogrammed, whereas augmented glycolysis and mitochondrial oxidation were reduced by XKS. As result of mTOR suppression, XKS reduced HIF-1α accumulation and blocked HIF-1α nuclear translocation, and thus reduced angiogenesis by downregulating Vegf gene expression.</p><p><strong>Conclusion: </strong>These results show that XKS modulated metabolic remodeling through the AMPK/mTOR cascade to restrain pathological cardiac hypertrophy. Our findings shed new light on the role of XKS in cardiac protection, particularly in the context of metabolic remodeling.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156309"},"PeriodicalIF":6.7,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health and economic evaluation of herbal medicines for heart failure: A population-based cohort study.","authors":"Jianbo Guo, Xinyu Lu, Pei Zhang, Ruolin Du, Chen Liu, Guang Chen, Xiangjun Yin, Tiantian Meng, Anqi Li, Haiyong Chen, Qingyong He","doi":"10.1016/j.phymed.2024.156310","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156310","url":null,"abstract":"<p><strong>Background: </strong>Heart failure (HF) represents an advanced stage of various cardiovascular disorders, with its elevated admission rates and resultant health economic burden posing an ongoing global concern.</p><p><strong>Purpose: </strong>To evaluate the health and economic benefits of herbal medicine (HM) for patients with HF.</p><p><strong>Study design: </strong>Population-based cohort study.</p><p><strong>Methods: </strong>A five-year retrospective cohort study was carried out at a nationally recognized hospital in China. The study utilized propensity score matching (PSM) to match patients with HF. Chi-square tests were used to analyze dichotomous variables, and t-tests were employed for continuous variables. Logistic regression was used to examine hospital readmission rates, while multiple linear regression was utilized to evaluate direct medical costs. Statistical significance was set at p < 0.05.</p><p><strong>Results: </strong>After implementing PSM, 1924 HF patients were included in the analysis. The study identified two significant risk factors affecting the readmission rates: age over 65 years (adjusted odds ratio (OR) = 1.25, 95 % confidence interval (CI) [1.02, 1.53]) and smoking (adjusted OR = 1.31, 95 % CI [1.01, 1.70]). Additionally, patients who received adjunctive HM treatment exhibited a significantly lower readmission rate compared to those without HM treatment (adjusted OR = 0.76, 95 % CI [0.64, 0.92]). Furthermore, the use of HM during patient hospitalization did not significantly impact direct medical expenses but instead provided positive health economic benefits (incremental cost-effectiveness ratio (ICER) = 98.52). Factors influencing direct routine medical costs included over 65 years of age (Coef = 60.78, 95 % CI [36.25, 85.31]), and cardiac function classification (New York Heart Association (NYHA) III: Coef = 1979.92, 95 % CI [1401.82, 2558.03]; NYHA IV: Coef = 6052.48, 95 % CI [5166.59, 6938.38]).</p><p><strong>Conclusions: </strong>The integration of HM in patients with HF reduced readmission rates without a notable increase in direct medical costs, and the expense of HM remains an economically range indicating positive health economic outcomes.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156310"},"PeriodicalIF":6.7,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygonatum sibiricum polysaccharide ameliorates skeletal muscle aging and mitochondrial dysfunction via PI3K/Akt/mTOR signaling pathway.","authors":"Yang Li, Zhongyuan Liu, Hongyu Yan, Tianle Zhou, Liming Zheng, Feng Wen, Guanghui Guo, Zhiwen Zhang","doi":"10.1016/j.phymed.2024.156316","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156316","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenia is currently a life-threatening disease for the elderly. Polygonatum sibiricum polysaccharide (PSP) has anti-oxidative stress and anti-inflammatory effects. However, the effects of PSP on skeletal muscle aging, myoblast differentiation and mitochondrial dysfunction through PI3K/Akt/mTOR signaling pathway has not been explored.</p><p><strong>Purpose: </strong>To explore the effects and related mechanisms of PSP on muscle aging, myoblast differentiation and mitochondrial dysfunction.</p><p><strong>Methods: </strong>The chemical components of Polygonatum sibiricum were determined using the UHPLC-MS/MS method. The common targets and biological pathways between PSP and sarcopenia were investigated by network pharmacology analysis. In vitro C2C12 cells experiments were performed to reveal the effects of PSP on muscle aging, myotube differentiation, and mitochondrial damage. In addition, in vivo experiments were designed with the mouse model of D-gal-induced aging to evaluate the ameliorative impact of PSP on the skeletal muscle mass and function.</p><p><strong>Results: </strong>Polygonatum sibiricum mainly included 466 bioactive components. Polygonatum sibiricum and sarcopenia had 278 common targets by network pharmacology analysis, which were associated with mitochondrial function and PI3K/Akt/mTOR pathway. In vitro experiment indicated that PSP significantly enhanced the viability of C2C12 cells and myotube differentiation by down-regulating p21, p53, p16, MuRF1 and Atrogin-1and up-regulating MyoD, Myogenin, and MyHC. However, the addition of LY294002, PI3K/Akt/mTOR pathway inhibitor, partially reversed the anti-aging and anti-oxidative stress effects of PSP. PSP also significantly improved mitochondrial membrane potential and decreased mitochondrial ROS levels by upregulating the phosphorylation of the PI3K/Akt/mTOR pathway. In vivo experimental data indicated that PSP significantly enhanced muscle strength, endurance, mass of skeletal muscle (quadriceps and gastrocnemius) and cross-sectional area (CSA) of skeletal muscle in D-gal induced aging mice.</p><p><strong>Conclusion: </strong>PSP exhibits significant ameliorative effects on skeletal muscle aging and atrophy, as well as mitochondrial dysfunction by activating the PI3K/Akt/mTOR signaling pathway. Our study uniquely investigates the effects of PSP on skeletal muscle aging and mitochondrial dysfunction with a specific focus on the PI3K/Akt/mTOR signaling pathway, which highlights the potential of PSP as a novel therapeutic agent for sarcopenia, offering an alternative to current treatment strategies.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156316"},"PeriodicalIF":6.7,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyphenol extract from Tagetes erecta L. flowers stimulates osteogenesis via β-catenin activation.","authors":"Sobarathne Senel Sanjaya, Jinkuk Park, Yung Hyun Choi, Hee Sun Park, Takayuki Sadanaga, Min-Jeong Jung, Gi-Young Kim","doi":"10.1016/j.phymed.2024.156313","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156313","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Osteoporosis, a prevalent bone disorder, results in reduced bone mineral density and mass. With minimal side effects, medicinal plant-based natural remedies are increasingly explored for osteoporosis. However, the osteogenic potential of Tagetes erecta L. flower, traditionally used for cardiovascular and renal diseases, has not yet been studied.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;This study investigates the osteogenic effects of the polyphenol-enriched extract from T. erecta L. flowers (TE) and its main components on osteoblast differentiation, with an emphasis on anti-osteoporotic activity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The osteogenic activity of TE was assessed in MC3T3-E1 preosteoblast cells, analyzing osteogenic alkaline phosphatase (ALP) activity via a colorimetric assay and mineralization through Alizarin Red S staining over 14 d. Expression levels of osteogenic markers-transcription factor osterix (SP7), runt-related transcription factor 2 (RUNX2), and ALP-were quantified through quantitative reverse transcription-polymerase chain reaction and western blotting. In vivo effects were evaluated using zebrafish larvae for bone formation and anti-osteoporotic properties. Vertebral development was visualized by staining mineralized structures with calcein or Alizarin Red S. Prednisolone (PDS) was administered to zebrafish larvae to model osteoporosis. Furthermore, molecular docking simulations were conducted to assess the binding affinity of TE components to the ATP-binding pocket of glycogen synthase kinase-3β (GSK-3β), and their inhibitory potential on GSK-3β kinase activity was quantified by in vitro kinase assays. Cellular thermal shift assay (CETSA) was performed to monitor direct bindings of TE and its main components to GSK3-3β.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;TE promoted vertebral and cranial bone formation in zebrafish larvae, elevating key osteogenic genes, such as sp7, runx2a, runx2b, and alpl. Among TE components, kaempferol and patuletin significantly enhanced vertebral formation, while isorhamnetin showed moderate effects. Patulitrin and quercetagetin did not increased vertebral formation. In MC3T3-E1 cells, TE increased ALP activity, mineralization, and the expression of SP7, RUNX2, and ALP. It also induced GSK-3β phosphorylation at serine 9 and promoted β-catenin nuclear translocation. Inhibition of β-catenin signaling reversed TE-induced osteogenic effects. Molecular docking suggested strong GSK-3β binding by TE components, with patuletin showing notable inhibition GSK-3β activity (half-maximal inhibitory concentration = 379.3 ng/mL) and enhancing vertebral formation. CETSA confirmed that TE and its main components, kaempferol and patuletin, degrades GSK-3β. Additionally, TE alleviated PDS-induced osteoporosis in both cellular and zebrafish models.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;By targeting GSK-3β and activating β-catenin-mediated pathways, TE shows promise as a novel anti-osteoporotic agent","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156313"},"PeriodicalIF":6.7,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Taraxasterol regulates p53 transcriptional activity to inhibit pancreatic cancer by inducing MDM2 ubiquitination degradation.","authors":"Anna Han, Jiajing Liu, Pan Du, Wenxuan Li, Haiyan Quan, Zhenhua Lin, Liyan Chen","doi":"10.1016/j.phymed.2024.156298","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156298","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer (PC) is a malignant tumor with complex development mechanisms and a poor prognosis. Taraxasterol (TAX), a pentacyclic triterpenoid plant sterol derived from Taraxacum mongolicum, has multiple biological activities including an anti-tumor effect. However, the mechanism by which TAX exerts its anticancer effects in PC remains unclear.</p><p><strong>Purpose: </strong>This study aimed to elucidate the molecular mechanism by which TAX suppresses the proliferation of PC.</p><p><strong>Methods: </strong>The intersection of TAX and PC targets was obtained through network pharmacology. RNA-seq was used to identify TAX-induced differentially expressed genes in PC. Molecular docking, CETSA, western blot analysis, and qRT-PCR were performed to confirm the effectiveness of targets. The influence of TAX on PC was assessed by analyzing proliferation, apoptosis, and the cell cycle via MTT assay, colony formation assay, and flow cytometry, respectively. Co-IP assay and immunofluorescence assay were used to evaluate the effect of TAX on targeted genes. A nude mouse xenograft model was constructed to determine the inhibitory effects of TAX on PC in vivo.</p><p><strong>Results: </strong>TAX suppressed PC cell proliferation by promoting apoptosis and inducing cell cycle arrest in vitro and in vivo. Mechanistically, TAX interacted with MDM2, a critical regulator of proliferation, and decreased its stability by inducing ubiquitin-mediated degradation, which facilitates the nuclear translocation of p53 and downregulation of CXCL5 transcription, ultimately suppressing PC cell proliferation.</p><p><strong>Conclusion: </strong>MDM2/p53/CXCL5 is the key pathway of TAX inhibiting the proliferation of PC cells.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156298"},"PeriodicalIF":6.7,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}